Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site

  • Bioorg Med Chem Lett. 2022 Mar 15;60:128571. doi: 10.1016/j.bmcl.2022.128571.
Nicholas L Yan  1 ,  Reji Nair  1 ,  Alan Chu  2 ,  Ian A Wilson  3 ,  Kristen A Johnson  2 ,  Gareth J Morgan  4 ,  Jeffery W Kelly  5
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 2. California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 3. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 4. Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; The Amyloidosis Center, Boston University School of Medicine, Boston, MA 02118, USA.
  • 5. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 35065233 DOI: 10.1016/j.bmcl.2022.128571
Abstract

In immunoglobulin light chain (LC) amyloidosis, the misfolding, or misfolding and misassembly of LC a protein or fragments thereof resulting from aberrant endoproteolysis, causes organ damage to patients. A small molecule "kinetic stabilizer" drug could slow or stop these processes and improve prognosis. We previously identified coumarin-based kinetic stabilizers of LCs that can be divided into four components, including a "linker module" and "distal substructure". Our prior studies focused on characterizing carbamate, hydantoin, and spirocyclic urea linker modules, which bind in a solvent-exposed site at the VL-VL domain interface of the LC dimer. Here, we report structure-activity relationship data on 7-diethylamino coumarin-based kinetic stabilizers. This substructure occupies the previously characterized "anchor cavity" and the "aromatic slit". The potencies of amide and urea linker modules terminating in a variety of distal substructures attached at the 3-position of this coumarin ring were assessed. Surprisingly, crystallographic data on a 7-diethylamino coumarin-based kinetic stabilizer reveals that the urea linker module and distal substructure attached at the 3-position bind a solvent-exposed region of the full-length LC dimer distinct from previously characterized sites. Our results further elaborate the small-molecule binding surface of LCs that could be occupied by potent and selective LC kinetic stabilizers.

Keywords
Amyloidosis; Crystal structure; Immunoglobulin; Kinetic stabilizer; Light chain; Proteolysis.
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